Whether the ATP sensitive potassium channel opener pinacidil can provide myocardial protective effects in prolonged isolated global ischemic rat heart was investigated. On modified isolated rat working heart model, 4...Whether the ATP sensitive potassium channel opener pinacidil can provide myocardial protective effects in prolonged isolated global ischemic rat heart was investigated. On modified isolated rat working heart model, 40 hearts were divided into four groups randomly: Hyperpolarized arrest H K solution containing pinacidil (50 μmol/L) (P1 and P2) and depolarized arrest St. Thomas' solution (S1 and S2) subjected to 15 ℃ hypothermia, 60 min (P1 and S1) or 120 min (P1 and S2) of ischemia and 30 min reperfusion. The experimental indices included cardioplegic efficiency, cardiac function, coronary blood flow, myocardial enzyme release, myocardial water and ATP content. Hyperpolarized arrest provided significantly better recovery of cardiac function than depolarized arrest. Postischemic coronary flow and myocardial ATP content were higher. The arrest time of electro mechanical activities were longer than depolarized arrest. There were no differences among the groups in myocardial water contents. The hyperpolarized arrest solution containing pinacidil can provide a marked myocardial protective effect during prolonged hypothermic myocardial ischemia.展开更多
Background Many studies have indicated that hyperpolarizing cardioplegia is responsible for myocardial preservation and researchers have suggested that the adenosine triphosphate-sensitive potassium channels （KATe） ...Background Many studies have indicated that hyperpolarizing cardioplegia is responsible for myocardial preservation and researchers have suggested that the adenosine triphosphate-sensitive potassium channels （KATe） were the end effectors of cardio-protection. But whether mitochondrial KATe plays an important role in hyperpolarizing cardioplegia is not apparent. The present study investigated the effect of hyperpolarizing cardioplegia containing pinacidil （a nonselective KATe opener） on ischemia/repeffusion injury in rat hearts, especially the role of mitochondrial KATe in pinacidil hyperpolarizing cardioplegia. Methods Sprague-Dawley rat hearts were Langendorff-perfused for 20 minutes with Krebs-Henseleit buffer at 37℃ before equilibration. Cardiac arrest was then induced in different treatments： there was no arrest and ischemia in the normal group, the control group were arrested by clamping the aorta, depolarizing caidioplegia （St. Thomas solution containing 16 mmol/L KCI） and hyperpolarizing cardioplegia groups used St. Thomas solution containing 0.05 mmol/L pinacidil and 5 mmol/L KCI to induce cardiac arrest in group hyperkalemic and group pinacidil, in group hyperkalemic ＋ 5-hydroxydecanote （5HD） and Pinacidil ＋ 5HD, 5HD （0.1 retool/L） was added to the above two solutions to block mitochondria KATe channels. Global ischemia was then administrated for 40 minutes at 37℃, followed by 30 minutes of reperfusion. At the end of equilibration and reperfusion, hemodynamics, ultrastructure, and mitochondrial function were measured. Results In the control group, ischemia/reperfusion decreased the left ventricular developed pressure, heart rate, coronary flow, mitochondrial membrane potential, impaired mitochondrial respiratory function, increased reactive oxygen species and left ventricular end diastolic pressure. Damage to myocardial ultrastructure was also evident. Both depolarized arrest and especially hyperpolarized cardioplegia significantly reduced these lesions. 5HD partially blocked the beneficial effects of pinacidil cardioplegia but showing no effects on hyperkalemic arrest. Conclusions Pinacidil cardioplegia provides better cardioprotection with preservation of hemodynamics, ultrastructure, and mitochondrial function than traditional cardioplegia. The mitochondria KATe channels may play an important role in the protection mechanism.展开更多
It has been found that the potassium channel dysfunction of the membrane of airway smooth muscle cells (ASMCs) is closely associated with proliferation of ASMCs.~1 Preliminary research has demonstrated that pinacidil,...It has been found that the potassium channel dysfunction of the membrane of airway smooth muscle cells (ASMCs) is closely associated with proliferation of ASMCs.~1 Preliminary research has demonstrated that pinacidil, an ATP sensitive potassium channel (K_(ATP)) opener, could play a remarkable role in the prevention and treatment of antigen induced bronchial asthma in guinea pigs.~2 (This study)was designed to investigate further the role and molecular mechanism of the proliferation of ASMCs: a chief pathological change of the nonacute phase of bronchial asthmatic episodes.展开更多
The transient receptor potential Ankyrin 1(TRPA1) cation channel is activated by various pungent and irritant compounds,and it also mediates the perception of noxious cold.Identification of different agonists for this...The transient receptor potential Ankyrin 1(TRPA1) cation channel is activated by various pungent and irritant compounds,and it also mediates the perception of noxious cold.Identification of different agonists for this channel is important for understanding its activation mechanism.Therefore,a screen for novel TRPA1 agonists was performed using an agonist-induced calcium influx assay.Out of 90 compounds screened,pinacidil was identified as a novel agonist for this channel.Pinacidil is a known opener of the K atp channel,for which it has an EC50 value of 1-3 μmol/L.In comparison,the EC50 value of pinacidil for TRPA1 is relatively high(260 μmol/L).Recombinant HEK-TRPA1 cells did not respond to P1075,another K atp channel opener,suggesting that the effect of pinacidil on TRPA1 was highly specific.Further studies revealed that the agonist activity of pinacidil could be blocked by the TRP channel inhibitors,ruthenium red and HC-030031.Using glutathione(GSH) and site-specific mutagenesis,we demonstrated that pinacidil could activate TRPA1 by covalent modification of the critical amino acids C619,C639 and C663 in the N-terminus of TRPA1.展开更多
Pinacidl(匹那地尔)为开放钾通道的新型抗高血压药的代表。其作用是使细胞膜钾通道开放,导致超极化,从而使平滑肌松弛,血管扩张,血压下降。其降血压效力与现有血管扩张药如肼笨哒嗪、哌唑嗪、硝苯吡啶等相当或略胜之。本品使用安全。主...Pinacidl(匹那地尔)为开放钾通道的新型抗高血压药的代表。其作用是使细胞膜钾通道开放,导致超极化,从而使平滑肌松弛,血管扩张,血压下降。其降血压效力与现有血管扩张药如肼笨哒嗪、哌唑嗪、硝苯吡啶等相当或略胜之。本品使用安全。主要不良反应为水肿。其它不良反应包括心悸、心率加速和暂时性 T 波变化。本品可使血脂降低,与噻嗪类利尿剂合用,可明显减轻其水肿副作用并增强其疗效。预期本品及其它钾通道开放剂今后将成为又一类新型抗高血压药。展开更多
基金This project was supported by a grant from EducationalMinistry Foundation of China (No.[2 0 0 1]34 5 )
文摘Whether the ATP sensitive potassium channel opener pinacidil can provide myocardial protective effects in prolonged isolated global ischemic rat heart was investigated. On modified isolated rat working heart model, 40 hearts were divided into four groups randomly: Hyperpolarized arrest H K solution containing pinacidil (50 μmol/L) (P1 and P2) and depolarized arrest St. Thomas' solution (S1 and S2) subjected to 15 ℃ hypothermia, 60 min (P1 and S1) or 120 min (P1 and S2) of ischemia and 30 min reperfusion. The experimental indices included cardioplegic efficiency, cardiac function, coronary blood flow, myocardial enzyme release, myocardial water and ATP content. Hyperpolarized arrest provided significantly better recovery of cardiac function than depolarized arrest. Postischemic coronary flow and myocardial ATP content were higher. The arrest time of electro mechanical activities were longer than depolarized arrest. There were no differences among the groups in myocardial water contents. The hyperpolarized arrest solution containing pinacidil can provide a marked myocardial protective effect during prolonged hypothermic myocardial ischemia.
基金This project was supported by a grant from the National Natural Science Foundation of China （No. 30460132）.
文摘Background Many studies have indicated that hyperpolarizing cardioplegia is responsible for myocardial preservation and researchers have suggested that the adenosine triphosphate-sensitive potassium channels （KATe） were the end effectors of cardio-protection. But whether mitochondrial KATe plays an important role in hyperpolarizing cardioplegia is not apparent. The present study investigated the effect of hyperpolarizing cardioplegia containing pinacidil （a nonselective KATe opener） on ischemia/repeffusion injury in rat hearts, especially the role of mitochondrial KATe in pinacidil hyperpolarizing cardioplegia. Methods Sprague-Dawley rat hearts were Langendorff-perfused for 20 minutes with Krebs-Henseleit buffer at 37℃ before equilibration. Cardiac arrest was then induced in different treatments： there was no arrest and ischemia in the normal group, the control group were arrested by clamping the aorta, depolarizing caidioplegia （St. Thomas solution containing 16 mmol/L KCI） and hyperpolarizing cardioplegia groups used St. Thomas solution containing 0.05 mmol/L pinacidil and 5 mmol/L KCI to induce cardiac arrest in group hyperkalemic and group pinacidil, in group hyperkalemic ＋ 5-hydroxydecanote （5HD） and Pinacidil ＋ 5HD, 5HD （0.1 retool/L） was added to the above two solutions to block mitochondria KATe channels. Global ischemia was then administrated for 40 minutes at 37℃, followed by 30 minutes of reperfusion. At the end of equilibration and reperfusion, hemodynamics, ultrastructure, and mitochondrial function were measured. Results In the control group, ischemia/reperfusion decreased the left ventricular developed pressure, heart rate, coronary flow, mitochondrial membrane potential, impaired mitochondrial respiratory function, increased reactive oxygen species and left ventricular end diastolic pressure. Damage to myocardial ultrastructure was also evident. Both depolarized arrest and especially hyperpolarized cardioplegia significantly reduced these lesions. 5HD partially blocked the beneficial effects of pinacidil cardioplegia but showing no effects on hyperkalemic arrest. Conclusions Pinacidil cardioplegia provides better cardioprotection with preservation of hemodynamics, ultrastructure, and mitochondrial function than traditional cardioplegia. The mitochondria KATe channels may play an important role in the protection mechanism.
文摘It has been found that the potassium channel dysfunction of the membrane of airway smooth muscle cells (ASMCs) is closely associated with proliferation of ASMCs.~1 Preliminary research has demonstrated that pinacidil, an ATP sensitive potassium channel (K_(ATP)) opener, could play a remarkable role in the prevention and treatment of antigen induced bronchial asthma in guinea pigs.~2 (This study)was designed to investigate further the role and molecular mechanism of the proliferation of ASMCs: a chief pathological change of the nonacute phase of bronchial asthmatic episodes.
基金supported by grants from the Ministry of Science and Technology (2007CB914200 and 2010DFA32140)the National Natural Science Foundation of China(31130028 and 30973514)Program of Introducing Talents of Discipline to Universities of Ministry of Education (B08029)
文摘The transient receptor potential Ankyrin 1(TRPA1) cation channel is activated by various pungent and irritant compounds,and it also mediates the perception of noxious cold.Identification of different agonists for this channel is important for understanding its activation mechanism.Therefore,a screen for novel TRPA1 agonists was performed using an agonist-induced calcium influx assay.Out of 90 compounds screened,pinacidil was identified as a novel agonist for this channel.Pinacidil is a known opener of the K atp channel,for which it has an EC50 value of 1-3 μmol/L.In comparison,the EC50 value of pinacidil for TRPA1 is relatively high(260 μmol/L).Recombinant HEK-TRPA1 cells did not respond to P1075,another K atp channel opener,suggesting that the effect of pinacidil on TRPA1 was highly specific.Further studies revealed that the agonist activity of pinacidil could be blocked by the TRP channel inhibitors,ruthenium red and HC-030031.Using glutathione(GSH) and site-specific mutagenesis,we demonstrated that pinacidil could activate TRPA1 by covalent modification of the critical amino acids C619,C639 and C663 in the N-terminus of TRPA1.
文摘Pinacidl(匹那地尔)为开放钾通道的新型抗高血压药的代表。其作用是使细胞膜钾通道开放,导致超极化,从而使平滑肌松弛,血管扩张,血压下降。其降血压效力与现有血管扩张药如肼笨哒嗪、哌唑嗪、硝苯吡啶等相当或略胜之。本品使用安全。主要不良反应为水肿。其它不良反应包括心悸、心率加速和暂时性 T 波变化。本品可使血脂降低,与噻嗪类利尿剂合用,可明显减轻其水肿副作用并增强其疗效。预期本品及其它钾通道开放剂今后将成为又一类新型抗高血压药。
